The Genetics of Clotting Disorders

A few months ago we were shocked to learn of the sudden death of news reporter, David Bloom. Subsequent details indicated the development of clots, causing a pulmonary embolism and sudden death in this young man. A recent article discussed this same case and suggested the possible cause as his being in a sedentary position for too long a period of time. While it is very true that lack of mobility, stretching and exercise can lead to clot formation, I would like to introduce you to possible genetic causes of an increased tendency to venous and/or arterial thrombotic or clotting events.

Venous thrombosis can be defined as deep vein thrombosis, characterized by a painful, swollen leg or as a pulmonary embolism, characterized by an irregular heartbeat, breathing difficulty, acute failure of the right side of the heart and sudden death. Annually there are 250,000-500,000 hospitalizations per year and 100,000 deaths per year due to thrombophilia.

The list of environmental factors that increase thrombotic risk is extensive. Included in this list are surgery, trauma, diabetes, obesity, hypertension, smoking and use of oral contraceptives.

Genetic involvement centers on three primary genes: the prothrombin gene on chromosome 11, Factor V Leiden on chromosome 1 and the MTHFR gene on chromosome 1. Sixty three percent of the cases of inherited thrombophilia are due to mutations in factor V Leiden or prothrombin. Factor V Leiden mutations are seen in 2-7% of the population and is the most common genetic cause of venous thrombosis (20-40% of cases). The MTHFR mutation is very common and is carried by 45-50% of the general population. Homozygosity for the C677T MTHFR mutation can be associated with increased levels of an amino acid called homocysteine, which may indicate an increased risk for coronary artery disease. Interestingly, taking folic acid, the same folic acid that is so effective in preventing neural tube defects can significantly reduce homocysteine levels.

Testing for these gene mutations is available at many genetic laboratories and should be considered if there is a personal or family history of deep vein thrombosis. Plasma homocysteine levels can also be determined and may serve as a possible early indicator of coronary artery disease.